Dow Louise F, Pathirage Rasangi, Erickson Helen E, Amani Edrees, Ronning Donald R, Trippier Paul C
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha Nebraska 68198 USA
Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center Omaha Nebraska 68198 USA.
RSC Med Chem. 2024 Nov 18. doi: 10.1039/d4md00733f.
Alzheimer's disease (AD) is estimated to affect over 55 million people across the world. Small molecule treatment options are limited to symptom management with no impact on disease progression. The need for new protein targets and small molecule hit compounds is unmet and urgent. Hydroxysteroid 17-β dehydrogenase type 10 (17β-HSD10) is a mitochondrial enzyme known to bind amyloid beta, a hallmark of AD, and potentiate its toxicity to neurons. Identification of small molecules capable of interacting with 17β-HSD10 may drive drug discovery efforts for AD. The screening compound BCC0100281 (1), was previously identified as an inhibitor of 17β-HSD10. Herein we report the first synthetic access to the hit compound following a convergent pathway starting from simple heterocyclic building blocks. The compound was found to be toxic to 'neuron-like' cells, specifically those of neuroblastoma origin, providing a potential hit compound for cancer drug discovery, wherein the protein is known to be overexpressed. However, assay of synthetic intermediates identified novel scaffolds with effect to rescue amyloid beta-induced cytotoxicity, showcasing the power of organic synthesis and medicinal chemistry to optimize hit compounds.
据估计，全球有超过5500万人受到阿尔茨海默病（AD）的影响。小分子治疗方案仅限于症状管理，对疾病进展没有影响。对新的蛋白质靶点和小分子命中化合物的需求尚未得到满足且十分迫切。17-β羟类固醇脱氢酶10型（17β-HSD10）是一种线粒体酶，已知它能结合淀粉样蛋白β（AD的一个标志）并增强其对神经元的毒性。鉴定能够与17β-HSD10相互作用的小分子可能推动AD的药物研发工作。筛选化合物BCC0100281（1）先前被鉴定为17β-HSD10的抑制剂。在此，我们报告了从简单的杂环构建单元出发，通过汇聚途径首次合成该命中化合物的方法。发现该化合物对“类神经元”细胞有毒性，特别是对神经母细胞瘤来源的细胞，这为癌症药物研发提供了一种潜在的命中化合物，其中已知该蛋白在癌症中过表达。然而，对合成中间体的检测鉴定出了具有挽救淀粉样蛋白β诱导的细胞毒性作用的新型支架，展示了有机合成和药物化学在优化命中化合物方面的力量。
